The proposed studies will investigate the effect of premature weaning on the regulation of cholesterol and lipoprotein metabolism in the adult guinea pig. Preliminary studies have shown that weaning 2 day old neonate guinea pig to a chow diet, as compared to controls weaned at 14-days of age, results in adult guinea pigs with elevated plasma cholesterol levels, alterations in the composition of plasma low density lipoproteins (LDL), elevated hepatic HMG-CoA reductase activities, and reduced expression of hepatic apo B/E receptors. These data demonstrate that premature weaning results in a number of significant alterations of adult lipid metabolism due to a process termed """"""""neonatal imprinting of metabolic memory"""""""". The proposed studies will expand these observations to determine the time frame of sensitivity to imprinting by premature weaning by testing effects of weaning at various time points between 2 and 14 days of age. Studies will also determine the effect of the premature weaning diet, saturated versus polyunsaturated fat either low or high in cholesterol, on the imprinting effects on adult sterol and lipoprotein metabolism in the guinea pig. Once the optimal time point and post-weaning diet have been determined, studies will be performed to determine the effects of neonatal imprinting by premature weaning on the homeostatic responses to changes in dietary fat (corn oil versus lard) and in dietary cholesterol. Studies will determine the effects on the regulation of hepatic and extrahepatic sterol synthesis (hepatic HMGCoA reductase activity, mass and mRNA levels; [3H]water incorporation into sterols), of low density lipoprotein (LDL) metabolism (hepatic apo B/E receptor levels, mass and mRNA; in vivo LDL kinetics and tissue uptake), and of other key parameters modulating endogenous sterol and lipoprotein metabolism (plasma cholesteryl ester transfer activity and hepatic cholesterol 7alpha-hydroxylase activity). These studies will determine the neonatal imprinting induced changes in hepatic sterol metabolism, plasma LDL kinetics and cholesteryl ester transfer, and modifications in gene regulation. The final set of studies will evaluate the metabolic changes induced by premature weaning in guinea pigs between the ages of 2 and 14 days. These studies are designed to investigate the effects of premature weaning on adult sterol and LDL metabolism in order to better understand the effects of breast feeding versus premature weaning as related to elevated plasma LDL cholesterol levels and resulting from decreased apo B/E receptor expression.
